Reagents for asymmetric allylation, aldol, and tandem aldol and allyation reactions

ABSTRACT

A new class of reagents and method of use of the reagents in the reaction of the reagents with electrophilic compounds. The invention in one embodiment is directed to a method for the formation of an alcohol of the formula (I). The method includes reacting a reagent of the formula (II) with an aldehyde of the formula R 10 CHO to form the alcohol. X 3  is one of O and C(R 4 )(R 5 ). Each of X 1  and X 2  is independently O or N—R. Each of C a  and C b  is independently an achiral center, an (S) chiral center or an (R) chiral center. R a  and R b  are (i) each independently C 1-10  alkyl, C 6-10  aryl or C 3-9  heteroaryl, or (ii) taken together to form a C 3 —C 4  alkylene chain which together with C a  and C b  forms a 5-membered or 6-membered aliphatic ring. R c  and R d  are each independently hydrogen, C 1-10  alkyl, C 6-10  aryl or C 3-9  heteroaryl. R is C 1-10  alkyl, C 6-10  aryl or C 3-9  heteroaryl. Each of R 1 , R 2 , R 3 , R 4 , R 5  is independently hydrogen, C 1 —C 10  alkyl, C 6-10  aryl, C 3-9  heteroaryl, C 1-10  alkoxy, C 6-10  aryloxy, C 1-10  dialkylamino, C 1-10  alkyl-C 6-10  arylamino, C 1-10  diarylamino, or halogen. R 6  is halogen, hydrogen, C 1-10  alkyl, C 6-10  aryl, C 3-9  heteroaryl, C 1-10  alkoxy, C 6-10  aryloxy, C 1-10  alkyl-C 6-10  arylamino, C 1-10  diarylamino, OSO 2 CF 3  or SR. R 10  may be C 1-10  alkyl, C 6-10  aryl, or C 3-9  heteroaryl.

This application claims priority to the following applications:International Patent Application No. PCT/US03/06308 filed on Mar. 3,2003 and published under International Publication No. WO 03/074534 onSep.12, 2003, of which the instant application is a National StageFiling under 35 U.S.C, § 371, and the provisional applications to whichInternational Patent Application No. PCT/US03/06308 also claimspriority, namely, U.S. Provisional Patent Application No. 60/360,987filed on Mar. 1, 2002 and U.S. Provisional Patent Application No.60/369,812, filed on Apr. 4, 2002 each of which are incorporated byreference in their entireties herein.

This work was supported by Grant No. GM58133 from the NationalInstitutes of Health (NIH).

FIELD OF THE INVENTION

The present invention relates to reagents which are useful forasymmetric allylations, aldols, and tandem aldol and allylationreactions. In particular, the presente invention relates to cyclicreagents containing a silicon atom which are useful for the preparationby asymmetric allylations, aldols, and tandem aldol and allylationreactions of chiral alcohols and hydrazines.

BACKGROUND OF THE INVENTION

Asymmetric additions of allyl groups and enolates to the carbonyl (C═O)group of aldehydes and to the C═N group of related electrophiliccompounds remains one of the most important and fundamental carbonyladdition reactions for the synthesis of optically active chiralcompounds containing a chiral carbon center bonded to an oxygen ornitrogen atom. Such compounds may have utility, for example, aspharmaceutically active compounds, or may be used to prepare otherpharmaceutically active compounds. Many highly enantioselectiveallylation reagents and catalysts have been developed, as described, forexample, in Brown, H. C. and Jadhav, P. K., J. Am. Chem. Soc., Vol. 105(1983), p. 2092; Jadhav, P. K., Bhat, K. S., Perumal P. T. and Brown, H.C., J. Org. Chem., Vol. 51 (1986), p. 432; Racherla, U. S. and Brown, H.C., J. Org. Chem., Vol. 56 (1991), p. 401; Roush, W. R., Walts, A. E.and Hoong, L. K., J. Am. Chem. Soc., Vol. 107 (1985), p. 8186; Roush, W.R. and Banfi, W. L., J. Am. Chem. Soc., Vol. 110 (1988), p. 3979;Hafner, A., Duthaler R. O., Marti, R., Ribs, G., Rothe-Streit, P. andSchwarzenbach, F., J. Am. Chem. Soc., Vol. 114 (1992), p. 2321; Wang,Z., Wang, D. and Sui, X., Chem. Commun. (1996), p. 2261; Wang, D., Wang,Z. G., Wang, M. W., Chen, Y. J., Liu, L. and Zhu, Y., Tetrahedron:Asymmetry, Vol. 10 (1999), p. 327; Zhang, L. C., Sakurai, H. and Kira,M., Chem. Lett. (1997), p. 129. Similarly, highly enantioselectiveenolate reagents have been developed, as described, for example, inPaterson, I., Lister, M. A. and McClure, C. K., Tetrahedron Lett., vol.27, (1986), p. 4787; Paterson, I. and Goodman, J. M., Tetrahedron Lett.,vol. 30, (1989), p. 997; Paterson, I.,Goodman, J. M., Lister, M. A.,Schumann, R. C., McClure, C. K. and Norcross, R. D., Tetrahedron, Vol.46, (1990), p. 4663; and Cowden, C. J. and Paterson, I., Org. React.Vol. 51, (1997), p. 1.

However, several problems have been found to be associated with theallylation and enolate reagents and catalysts of the prior art,including the expense of preparation, the instability of the reagents orthe catalysts, the need for using the reagents or the catalysts in situor shortly after their preparation, the toxicity of the reagents and thebyproducts of the reactions of the reagents and the catalysts withaldehydes, and the ease of separation and purification of the reactionproducts. A generally applicable method for the allylation and theaddition of enolates to aldehydes and related electrophilic compoundsrequires easily and inexpensively formed, stable, and storable reagentsand catalysts, reagents and byproducts having little or no toxicity, andeasy separation and purification of the products formed. A methodcombining all these characteristics has until now proven elusive.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a new classof reagents and method of use of the reagents that solves theabove-described problems of the prior art, and there is further providedexcellent enantioselectivities in the reaction of the reagents withelectrophilic compounds.

The invention in a first embodiment is a method for the formation of anallylation reagent of formula

The method includes reacting a silane of formula

with a compound of formula

to form the allylation reagent of formula (1). Each of X₁ and X₂ isindependently O or N—R. Each of C_(a) and C_(b) is independently anachiral center, an (S) chiral center or an (R) chiral center. R_(a) andR_(b) are (i) each independently C₁₋₁₀ alkyl, C₆₋₁₀ aryl or C₃₋₉heteroaryl, or (ii) taken together to form a C₃-C₄ alkylene chain whichtogether with C_(a) and C_(b) forms a 5-membered or 6-membered aliphaticring. R_(c) and R_(d) are each independently hydrogen, C₁₋₁₀ alkyl,C₆₋₁₀ aryl or C₃₋₉ heteroaryl. R⁶ of formulas (1) and (2) is a halogen,hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ dialkylamino,C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₁₋₁₀ diarylamino, or SR. R is C₁₋₁₀ alkyl,C₆₋₁₀ aryl or C₃₋₉ heteroaryl. Each of R¹, R², R³, R⁴, R⁵ of formulas(1) and (2) is independently hydrogen, C₁-C₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino, C₁₋₁₀alkyl-C₆₋₁₀ arylamino, C₁₋₁₀ diarylamino, or halogen.

The invention in another embodiment is a reagent of formula

where X₃ is one of O and C(R⁴)(R⁵) and X₁, X₂, C_(a), C_(b), R, R_(a),R_(b), R_(c)R_(d), R¹, R², R³, R⁴, R⁵ are as defined above in connectionwith formulas (1) and (2). R⁶ in formula (4) is halogen, hydrogen, C₁₋₁₀alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₁₋₁₀ diarylamino,—O—C(R⁹)═C(R⁷)(R⁸), OSO₂CF₃ or SR. Each of R⁷, R⁸ and R⁹ are defined inthe same way as R¹, R², R³, R⁴, and R⁵ in connection with formulas (1)and (2).

The invention in another embodiment is a method for the formation of afirst reagent of formula

The method includes reacting a second reagent of formula

with one equivalent of a lithium enolate of the formulaLi—O—C(R³)═C(R¹)(R²) to form the first reagent. Each of X₁ and X₂ isindependently O or N—R. Each of C_(a) and C_(b) is independently anachiral center, an (S) chiral center or an (R) chiral center. R_(a) andR_(b) are (i) each independently C₁₋₁₀ alkyl, C₆₋₁₀ aryl or C₃₋₉heteroaryl, or (ii) taken together to form a C₃-C₄ alkylene chain whichtogether with C_(a) and C_(b) forms a 5-membered or 6-membered aliphaticring. R_(c) and R_(d) are each independently hydrogen, C₁₋₁₀ alkyl,C₆₋₁₀ aryl or C₃₋₉ heteroaryl. R⁶ is a halogen, hydrogen, C₁₋₁₀ alkyl,C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀arylamino, C₁₋₁₀ diarylamino, O—C(R³)═C(R¹)(R²), or SR. R is C₁₋₁₀alkyl, C₆₋₁₀ aryl or C₃₋₉ heteroaryl. Each of R¹, R², and R³, isindependently hydrogen, C₁-C₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino,C₁₋₁₀ diarylamino, or halogen.

The invention in another embodiment is a method for the formation of analcohol of formula

The method includes reacting a reagent of formula

with an aldehyde of formula R¹⁰CHO to form the alcohol of formula (7),where X₃ is one of O and C(R⁴)(R⁵) and X¹, X₂, C_(a), C_(b), R, R_(a),R_(b), R_(c). R_(d), R¹,R², R³, R⁴, and R⁵ are as defined above inconnection with formulas (1), (2) and (3). R⁶ is a halogen, hydrogen,C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy,C₁₋₁₀ dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₁₋₁₀ diarylamino,OSO₂CF₃ or SR. R¹⁰ is C₁₋₁₀ alkyl, C₆₋₁₀ aryl, or C₃₋₉ heteroaryl.

The invention in another embodiment is a method for the formation of acompound of formula

The method includes reacting a reagent of formula

with a compound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹. X₃ is one of O andC(R⁴)(R⁵). X₄ is O or NH. X¹, X₂, C_(a), C_(b), R, R_(a), R_(b), R_(c).R_(d), R¹, R², R³, R⁴, and R⁵ are as defined above in connection withformulas (1), (2) and (3). R⁶ is a halogen, hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀aryl, C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino,C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₁₋₁₀ diarylamino, OSO₂CF₃ or SR. R¹¹ ishydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, or C₃₋₉ heteroaryl, R¹² is C₁₋₁₀alkyl, C₆₋₁₀ aryl or C₃₋₉ heteroaryl. R¹⁴ is hydrogen, C₁₋₁₀ alkyl,C₆₋₁₀ aryl, or C₃₋₉ heteroaryl.

The invention in another embodiment is a method for the formation of afirst allylation reagent of formula

The method includes reacting a second allylation reagent of formula

with an alcohol of the formula H—O—R¹³ in the presence of a base to formthe first allylation reagent of formula (11). X¹, X₂, C_(a), C_(b), R,R_(a), R_(b), R_(c) , R_(d), R¹, R², R³, R⁴, and R⁵, are as definedabove in connection with formulas (1), (2) and (3). R⁶ is a halogen orOSO₂CF₃. R¹³ is C₁-C₁₀ alkyl, C₆₋₁₀ aryl, or C₃₋₉ heteroaryl.

The invention in another embodiment is a method for the formation of afirst allylation reagent of formula

The method includes reacting a second allylation reagent of formula

with a lithium enolate of the formula Li—O—C(R⁹)═C(R⁷)(R⁸) to form thefirst allylation reagent. X¹, X₂, C_(a), C_(b), R, R_(a), R_(b), R_(c),R_(d), R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R⁹ are as defined above inconnection with formulas (1), (2) and (3). R⁶ is a halogen or OSO₂CF₃.

The invention in another embodiment is a method for the formation of afirst reagent of formula

The method includes reacting a second reagent of formula

with two equivalents of a lithium enolate of the formulaLi—O—C(R³)═C(R¹)(R²) to form the first reagent of formula (15). X₁, X₂and R are as defined above in connection with formulas (1), (2) and (3).Each of C_(a) and C_(b) is independently an achiral center, an (S)chiral center or an (R) chiral center. R_(a) and R_(b) are (i) eachindependently C₁₋₁₀ alkyl, C₆₋₁₀ aryl or C₃₋₉ heteroaryl, or (ii) takentogether to form a C₃-C₄ alkylene chain which together with C_(a) andC_(b) forms a 5-membered or 6-membered aliphatic ring. R_(c) and R_(d)are each independently hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl or C₃₋₉heteroaryl. Each of R¹, R², and R³, is independently hydrogen, C₁-C₁₀alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₁₋₁₀ diarylamino, orhalogen.

The invention in another embodiment is a method for the formation of adiol of formula

The method includes reacting a reagent of formula

with an aldehyde of formula R¹⁰CHO to form the diol of formula (17). X₃is one of O and C(R⁴)(R⁵). X¹, X₂, C_(a), C_(b), R, R_(a), R_(b), R_(c),R_(d), R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R⁹ are as defined above inconnection with formulas (1), (2), (3) and (4). R¹⁰ is C₁₋₁₀ alkyl,C₆₋₁₀ aryl, or C₃₋₉ heteroaryl.

The invention in another embodiment is a method for the formation of acompound of formula

The method includes reacting a reagent of formula

with a compound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ to obtain thecompound of formula (19). X₃ is one of O and C(R⁴)(R⁵). X₄ is one of NHand O. X¹, X₂, C_(a), C_(b), R, R_(a), R_(b), R_(c). R_(d), R¹, R², R³,R⁴, R⁵, R⁷, R⁸ and R⁹ are as defined above in connection with formulas(1), (2), (3) and (4). R¹¹ is hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, or C₃₋₉heteroaryl. R¹² is C₁₋₁₀ alkyl, C₆₋₁₀ aryl or C₃₋₉ heteroaryl. R¹⁴ ishydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, or C₃₋₉ heteroaryl.

In the foregoing formulas (1)-(20), the double bond between C(R³) andC(R¹)(R²), the double bond between X and C(R³), and the double bondbetween C(R⁹) and C(R⁸)(R⁷) may each be an (E) double bond, a (Z) doublebond, or a double bond that does not exhibit (E)/(Z) isomerism. In thecompound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹, the double bond between Cand N may be an (E) double bond or a (Z) double bond.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the ¹H NMR spectrum of allylation reagent 3.

FIG. 2 shows the ¹H NMR spectrum of allylation reagent 10.

FIG. 3 shows a chiral HPLC analysis of the alcohol obtained byallylation of benzaldehyde with allylation reagent 3 and of thecorresponding racemic alcohol.

FIG. 4 shows a chiral HPLC analysis of the alcohol obtained byallylation of cinnamaldehyde with allylation reagent 3 and of thecorresponding racemic alcohol.

FIG. 5 shows a chiral HPLC analysis of the alcohol obtained byallylation of dihydrocinnamaldehyde with allylation reagent 3 and of thecorresponding racemic alcohol.

FIG. 6 shows a ¹⁹F NMR (C₆D₆, 282 MHz) spectrum of the Mosher ester ofthe alcohol obtained by allylation of isovaleraldehyde with allylationreagent 3 and of the corresponding racemic alcohol.

FIG. 7 shows a ¹⁹F NMR (C₆D₆, 282 MHz) spectrum of the Mosher ester ofthe alcohol obtained by allylation of cyclohexanecarboxaldehyde withallylation reagent 3 and of the corresponding racemic alcohol.

FIG. 8 shows a ¹⁹F NMR (C₆D₆, 282 MHz) spectrum of the Mosher ester ofthe alcohol obtained by allylation of pivaldehyde with allylationreagent 3 and of the corresponding racemic alcohol.

FIG. 9 shows a ¹⁹F NMR (C6D₆, 282 MHz) spectrum of the Mosher ester ofthe alcohol obtained by allylation of benzyloxyacetaldehyde withallylation reagent 3 and of the corresponding racemic alcohol.

FIG. 10 shows a ¹⁹F NMR (C₆D₆, 282 MHz) spectrum of the Mosher ester ofthe alcohol obtained by allylation oftert-Butyldimethylsilyloxyacetaldehyde with allylation reagent 3 and ofthe corresponding racemic alcohol.

FIG. 11 shows the ¹H NMR spectrum of allylation reagent (R,R)-21.

FIG. 12 shows a chiral HPLC analysis of the alcohol obtained byallylation of 3-(Benzyloxy)propionaldehyde with allylation reagent(R,R)-21 and of the corresponding racemic alcohol.

FIG. 13 shows a chiral HPLC analysis of the alcohol obtained byallylation of 3-p-anisaldehyde with allylation reagent (R,R)-21 and ofthe corresponding racemic alcohol.

FIG. 14 shows a chiral HPLC analysis of the alcohol obtained byallylation of 3-p-CF₃-benzaldehyde with allylation reagent (R,R)-21 andof the corresponding racemic alcohol.

FIG. 15 shows a chiral HPLC analysis of the alcohol obtained byallylation of 3-trans-2-hexenal with allylation reagent (R,R)-21 and ofthe corresponding racemic alcohol.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl”, as used herein, unless otherwise indicated, refers toa monovalent aliphatic hydrocarbon radical having a straight chain,branched chain, monocyclic moiety, or polycyclic moiety or combinationsthereof, wherein the radical is optionally substituted at one or morecarbons of the straight chain, branched chain, monocyclic moiety, orpolycyclic moiety or combinations thereof with one or more substituentsat each carbon, where the one or more substituents are independentlyC₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₆₋₁₀ aryloxy,C₁-C₁₀ dialkylamino, or silyloxy in which the silicon has threesubstituents, where each substituent is independently hydrogen, C₁₋₁₀alkyl, C₆₋₁₀ aryl or C₃₋₉ heteroaryl, or halogen. The alkyl group maycontain one or more carbon-carbon double bonds, one or morecarbon-carbon triple bonds, or a combination thereof Examples of “alkyl”groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, methoxymethyl,phenylmethyl, 4-bromophenylmethyl, 4-methoxyphenylmethyl, phenoxymethyl,dimethylaminomethyl, chloromethyl, 2-phenylethyl, (E)- and(Z)-2-phenylethenyl (Ph-CH═CH—), benzyloxymethyl, and the like.

The term “halogen”, as used herein, means chlorine (Cl), fluorine (F),iodine (I) or bromine (Br).

The term “alkoxy”, as used herein, means “alkyl-O—”, wherein “alkyl” isdefined as above and O represents oxygen. Examples of “alkoxy” groupsinclude methoxy, ethoxy, n-butoxy, tert-butoxy, and alkoxy groups inwhich the alkyl group is halogenated, such as alkoxy groups in which thealkyl group is fluorinated, including, for example, trifluoroethoxy and1-trifluoromethyl-2-trifluoroethoxy.

The term “alkylthio”, as used herein, means “alkyl-S—”, wherein “alkyl”is defined as above and S represents sulfur. Examples of “alkylthio”groups include methylthio, ethylthio, n-butylthio, and tert-butylthio.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical obtained from an aromatic hydrocarbon by removal of onehydrogen from a carbon of the aromatic hydrocarbon, wherein the radicalis optionally substituted at between one and three carbons with asubstituent at each carbon, where the substituent at each carbon isindependently C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy,C₁-C₁₀ dialkylamino, or halogen. Examples of “aryl” groups includephenyl, 1-naphthyl, 2-naphthyl, o-, m-, and p-methylphenyl, o-, m-, andp-methoxyphenyl, o-, m-, and p-diphenyl, o-, m-, and p-phenoxyphenyl,and o-, m-, and p-chlorophenyl.

The term “heteroaryl”, as used herein, unless otherwise indicated,includes an organic radical obtained from a heteroaromatic hydrocarbonhaving a heteroaromatic ring and one or two heteroatoms in theheteroaromatic ring by removal of one hydrogen from a carbon of theheteroaromatic hydrocarbon, wherein one or two heteroatoms are selectedfrom the group consisting of O, N and S the radical is optionallysubstituted at between one and three carbons, at the one or twoheteroatoms, or at a combination thereof with a substituent at eachcarbon, heteroatom or combination thereof, where the substituent isindependently C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy,C₁-C₁₀ dialkylamino, C₁₀ alkoxycarbonyl, or halogen. Examples of“heteroaryl” groups include 2-furyl, 3-furyl, 2-thiophenyl, 3-indolyl,3-(N-t-butoxycarbonyl)-indolyl, 2-pyridyl, 3-pyridyl,2-chloro-5-pyridyl, 2-pyrrolyl and 2-(N-t-butoxycarbonyl)-pyrrolyl.

The term “aryloxy”, as used herein, means “aryl-O—”, wherein “aryl” isdefined as above and O represents oxygen. Examples of “aryloxy” groupsinclude phenoxy, 1-naphthoxy, and 2-naphthoxy.

The term “dialkylamino”, as used herein, means “alkyl-N-alkyl”, wherein“alkyl” is defined as above and N represents nitrogen. The two alkylgroups in the dialkylamino group may be the same or different. The term“C₁₋₁₀ dialkylamino” as used herein is intended to denote a dialkylaminogroup in which each of the two alkyl groups is a C₁₋₁₀ alkyl group.Examples of “dialkylamino” groups include dimethylamino, diethylamino,and ethylmethylamino.

The term “alkylarylamino”, as used herein, means “alkyl-N-aryl”, wherein“alkyl” and “aryl” are defined above and N represents nitrogen. The term“C₁₋₁₀ alkyl-C₆₋₁₀ arylamino” as used herein is intended to denote analkylarylamino group in which the alkyl group is a C₁₋₁₀ alkyl group andthe aryl group is a C₆₋₁₀ aryl group. An example of “alkylarylamino”group is methylphenylamino.

The term “diarylamino”, as used herein, means “aryl-N-aryl”, wherein“aryl” is defined as above and N represents nitrogen. The two arylgroups may be the same or different. The term “C₆₋₁₀ diarylamino” asused herein is intended to denote a diarylamino group in which each ofthe two aryl groups is a C₆₋₁₀ aryl group. An example of a “diarylamino”group is diphenylamino.

The term “alkylene chain” as used herein, unless otherwise indicated,refers to a monovalent aliphatic hydrocarbon diradical having a straightchain, branched chain, monocyclic, or polycyclic moiety or combinationsthereof, wherein the diradical is optionally substituted at one or morecarbons with one or more substituents at each carbon, where the one ormore substituents are independently C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₆₋₁₀aryl, C₆₋₁₀ aryloxy, C₁-C₁₀ dialkylamino, or halogen. The alkylene chainmay contain one or more carbon-carbon double bonds. Examples of alkylenechains include —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, and —CH₂—CH═CH—CH₂—.

The term “base” as used herein, unless otherwise indicated, refers to acompound capable of removing a proton from an acidic group such as an—OH group. Exemplary bases include mono-, di-, and trialkylamines, suchas, for example, diazabicycloundecene (DBU), diazabicyclononene (DBN)and triethylamine.

Exemplary silanes which may react with compounds of formula (3)according to the method of the invention include allyltrichlorosilane,allylmethyldichlorosilane, allylphenyldichlorosilane, and silanes havingthe formula CH₂═CH—CH₂SiCl₂Y, where Y═I, Br, F, OSO₂CF₃, C₁₋₁₀ alkoxy,C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino, or C₁₋₁₀ alkylthio.

In an exemplary embodiment of the invention, C_(a) and C_(b) are achiralcenters in the compound of the formula (3) and the reagents of theinvention are achiral compounds. In this embodiment, the diols formedfrom the reagents of the invention according to the method of theinvention are formed diastereoselectively.

In another exemplary embodiment of the invention, C_(a) and C_(b) arechiral centers in the compound of the formula (3) and the reagents ofthe invention are chiral compounds. In this embodiment, the homoallylicalcohols and the diols formed from the reagents of the inventionaccording to the method of the invention are formed enantioselectively,and the diols are also formed diastereoselectively. As used herein, theterm “enantioselectively” refers to forming a first of two enantiomersin an amount in excess of the second enantiomer. As used herein, theterm “diastereoselectively” refers to forming a first of two or morediastereomers an amount in excess of the remaining diastereomer ordiastereomers. The term “enantiomeric excess” denotes the amount bywhich the first enantiomer is in excess of the second enantiomer. Theterm “diastereomeric excess” denotes the amount by which the firstdiastereomer is in excess of the remaining diastereomer ordiastereomers.

The compounds of formula (3) may include, for example, compounds inwhich R_(a)and R_(b)are independently methyl or phenyl, and in whichR_(c)and R_(d)are independently methyl or hydrogen. For example, thecompounds of formula (3) include aminoalcohols (1S, 2S)-pseudoephedrine,(1R, 2R)-pseudoephedrine. The compounds of formula (3) also include theaminoalcohols shown in Chart 1, which may react with, for example,allyltrichlorosilane to give the corresponding reagents.

Exemplary aminoalcohols further include compounds of the formula (3) inwhich each of R_(a) and R_(b) is independently methyl or phenyl, X₂═Oand X₁═NR, where R is methyl, benzyl, or phenyl.

Exemplary compounds of formula (3) also include diols, including pinacol((CH₃)₂COH)₂ and chiral diols such as, for example, diol 28, having thefollowing formula:

Reaction of 28 with allyltrichlorosilane leads to the formation ofchiral reagent 29, as shown in the following equation.

The compounds of formula (3) also include, for example, compounds inwhich R_(a) and R_(b) taken together form a C₄ alkylene chain whichtogether with C_(a) and C_(b) forms a 6-membered aliphatic ring. Forexample, compounds of formula (3) include the diamine(1R,2R)-N,N-Dibenzyl-cyclohexane-1,2-diamine.

In one embodiment, the reaction between the silane and the compound offormula (3) takes place in the absence of a catalyst. The reaction mayalso take place in the absence of an additional reagent. In anotherembodiment, the reaction between the silane and the compound of formulaI takes place in the presence of a catalyst.

In an exemplary embodiment of the invention, in the reagent having theformula (10)

X₃═C(R⁴)(R⁵) and the reagent is an allylation reagent. The allylationreagent may be a stable compound which does not decompose when stored ata temperature lower or equal to 25° C. for a period of time of up toseveral weeks, such as, for example, a period of time of two months.

As an example, when allyltrichlorosilane was treated with the diolpinacol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in CH₂Cl₂,allylation reagent 1 was formed in accordance with Scheme 1. Compound 1was purified by distillation and obtained with 70% yield.

As another example, the reaction of the aminoalcohol(1S,2S)-pseudoephedrine with allyltrichlorosilane and Et₃N in CH₂Cl₂allowed the isolation of chiral allylation reagent 3 as an approximately2:1 mixture of diastereomers with 88% yield, as shown in Scheme 1. 3 maybe purified by distillation. Reagent 3 is stable and may be stored forseveral weeks without appreciable decomposition. The ¹H NMR spectrum ofreagent 3, which is shown in FIG. 1, is in agreement with the structureof reagent 3.

Reagent 3 is available in both enantiomeric form, which may be obtainedby reaction with allyltrichlorosilane of (1S,2S)-pseudoephedrine and of(1R,2R)-pseudoephedrine, respectively, both of which are inexpensivestarting materials.

The reaction between the reagent having formula (8)

and the aldehyde R¹⁰CHO may be performed using a solvent which may be,for example, toluene, tetrahydrofuran (THF), N,N-dimethylformamide(DMF), ethyl acetate (EtOAc), dichloromethane (CH₂Cl₂), hexane, t-butylmethyl ether (t-BuOMe), diethyl ether (Et₂O), acetonitrile (CH₃CN), andbenzene. In a preferred embodiment, the solvent is toluene. In anexemplary embodiment, the concentration of the aldehyde in the solventmay range from 0.05 M to 0.5 M. For example, a concentration of about0.2 M aldehyde may be used. In another exemplary embodiment, thereaction may be performed in the absence of solvent.

The reaction may be performed at a temperature ranging from about −78°C. to about 25° C. In a preferred embodiment, the temperature is about−10° C. The reaction is preferably performed in the absence of acatalyst.

The group R¹⁰ in the aldehyde, which is a C₁₋₁₀ alkyl or C₆₋₁₀ arylgroup, may be, for example, a methyl group, a t-butyl group, or a phenylgroup.

When the reagent is an allylation reagent (X═C(R⁴)(R⁵)), the product ofthe reaction is a homoallylic alcohol. As an example, the reaction ofreagent 1 with benzaldehyde (R¹⁰=phenyl) gave alcohol 2, as shown inScheme 2, in racemic form. The reaction of reagent 3 with benzaldehydein benzene at room temperature gave the S enantiomer of alcohol 2 (2(S))with 81% enantiomeric excess (ee), in accordance with Scheme 2.

Reagent 3 may be reacted with several other exemplary aldehydes, asshown in Scheme 3. Thus, for example, dihydrocinnamaldehyde wasallylated to give alcohol 4(R) with 88% ee, cinnamaldehyde to givealcohol 5(S) with 78% ee, benzyloxyacetaldehyde to give alcohol 6(S)with 88% ee and cyclohexanecarboxaldehyde to give alcohol 7(S) with 86%ee. In each case, the chiral alcohol is readily isolated upon completionof the allylation reaction, which typically requires about 12-16 hours,by adding 1 M HCl and ethyl acetate to the reaction mixture. Theresulting mixture is stirred for 15 minutes. An aqueous phase and anorganic phase are formed. The aqueous phase and the organic phase areseparated. The organic phase is then concentrated to give the chiralalcohol. The pseudoephedrine originally used to form reagent 3 accordingto Scheme 2 is regenerated upon addition of the 1 M HCl, and remains inthe aqueous phase after the aqueous phase and the organic phase areseparated. The pseudoephedrine may be recovered from the aqueous phaseand used to prepare additional amounts of reagent 3.

FIGS. 3-5 illustrate chiral high performance liquid chromatography(HPLC) analyses of the alcohols obtained by allylation with allylationreagent 3 of benzaldehyde, cinnamaldehyde and dihydrocinnamaldehyde,respectively. In each of FIGS. 3-5, the chiral HPLC analysis of thecorresponding racemic alcohol is also shown. FIGS. 6-10 show the ¹⁹F NMR(C₆D₆, 282 MHz) spectra of the Mosher esters of the alcohols obtained byallylation with allylation reagent 3 of isovaleraldehyde,cyclohexanecarboxaldehyde, pivaldehyde, benzyloxyacetaldehyde andtert-butyldimethylsilyloxyacetaldehyde, respectively. As shown in eachof FIGS. 3-10, one optical isomer of the alcohol product is formed inexcess of the other optical isomer, thereby showing that each reactionis enantioselective.

The aldehyde:reagent ratio may vary from about 1.5:1 to about 5:1, whichis an exemplary range of ratios for the reaction of inexpensivealdehydes, or the aldehyde:reagent ratio may be about 1:1.5, which is anexemplary ratio for expensive aldehydes. In an exemplary embodiment ofthe invention, the asymmetric allylations shown in Schemes 2 and 3 maybe performed using 1.5 equivalents of reagent 3 for every equivalent ofthe aldehyde.

Additional exemplary chiral allylation reagents include reagents 8 and9, which may be formed in accordance with Scheme 4, and which react withbenzaldehyde to give 1-phenyl-3-buten-1-ol with an enantioselectivity of42% and 58%, respectively.

The allylation reagents of the invention may also be formed fromdiamines, including chiral 1,2-diamines. Exemplary chiral diaminesinclude diamines having the formula (3) in which X₂ and X₁ are the samegroup NR, where R is methyl, benzyl, or phenyl; alternatively, X₂ and X₁may be two different groups NR′ and NR″, where each of R′ and R″ isindependently C₁₋₁₀ alkyl, C₆₋₁₀ aryl, or C₃₋₉ heteroaryl. For example,the reaction of (1R,2R)-N,N-Dibenzyl-cyclohexane-1,2-diamine withallyltrichlorosilane and DBU (diazabicycloundecene) in CH₂Cl₂ gavechiral allylation reagent 10, as shown in Scheme 5, with 99% crude yieldand in sufficient purity for use in the allylation reaction. The ¹H NMRspectrum of reagent 10, shown in FIG. 2, is in agreement with thestructure of reagent 10. Reaction of reagent 10 with benzaldehyde inbenzene for 72 hours led to the production of alcohol 2(S) in 51% yieldand 90% ee. Accordingly, the reaction of reagent 10 with aromatic andconjugated aldehydes provides high enantioselectivity.

In the allylation reagents formed from chiral 1,2-diamines, eachnitrogen atom of the 1,2-diamine fragment may be substituted with anarylmethyl (Ar—CH₂—) group in which the aryl group may be, for example,a phenyl group having a substituent para to the CH₂ group. For example,as shown in Table 1, the arylmethyl group may be p-bromophenylmethyl orp-methoxyphenylmethyl. The ¹H NMR spectrum of allylation reagent(R,R)-21, in which the arylmethylgroup is p-bromophenylmethyl, is shownin FIG. 11. FIGS. 12-15 show chiral HPLC analyses of the alcoholsobtained by allylation with allylation reagent (R,R)-21 of3-(Benzyloxy)propionaldehyde, p-anisaldehyde, p-CF₃-benzaldehyde andtrans-2-bexenal, respectively. In each of FIGS. 12-15, the chiral HPLCanalysis of the corresponding racemic alcohol is also shown. Each ofFIGS. 12-15 shows that one optical isomer of the alcohol product isformed in excess of the other optical isomer, thereby showing that eachreaction is enantioselective.

The reaction of allylation reagent (R,R)-21 with the aldehydes shown inTables 2 and 3, proceeds with high yield and enantioselectivity.Moreover, as shown in Scheme 6, Aldehyde 22 reacts with reagents(R,R)-21 and (S,S)-21 to give, respectively, syn β-benzyloxy alcohol 23and anti β-benzyloxy alcohol 24.

TABLE 1 Optimization of the Diamine Auxiliary.

entry^([a]) X R yield(%)^([b]) ee(%)^([c]) H PhCH₂CH₂ 79 96 H Ph 61 94OMe PhCH₂CH₂ 77 98 Br PhCH₂CH₂ 90 98 Br Ph 69 98 ^([a])Reactions runwith silane (1.0 equiv) and aldehyde (1.0 equiv) in CH₂Cl₂ at −10° C.for 20 h. ^([b])Isolated yield. ^([c])Determined by chiral HPLC analysisor by the Mosher ester method. See the supporting information.

TABLE 2 Enantioselective Allylation of Aliphatic Aldehydes.

entry^([a]) aldehyde product yield(%)^([b]) ee(%)^([c])

90 98

80^([d]) 96

93 96

67 97

87 98

61 98 ^([a])Reactions run with silane 3 (1.0 equiv) and aldehyde (1.0equiv) in CH₂Cl₂ at −10° C. for 20 h. ^([b])Isolated yield.^([c])Determined by chiral HPLC analysis or by the Mosher ester method.See the supporting information. ^([d])Due to product volatility, analtermative workup and purification was employed. See the supportinginformation.

TABLE 3

entry^([a]) aldehyde product yield(%)^([b]) ee(%)^([c])

69 98 [d]

62 96

66 96 [e]

66 96 [e]

71^([f]) 95 ^([a])Reactions: run with silane 3 (1.0 equiv) and aldehyde(1.0 equiv) in CH₂Cl₂ at −10° C. for 20 h. ^([b])Isolated yield.^([c])Determined by chiral HPLC analysis or by the Mosher ester method.See the supporting information. ^([d])Reaction run for 60 h.^([e])Reaction run at 8° C. for 72 h. ^([f])Due to product volatility,an alternative workup and purification was employed. See the supportinginformation.

In another embodiment of the invention, the reagent is an allylationreagent and has formula (11)

where OR¹³ is an alkoxy group, and R¹³ is C₁-C₁₀ alkyl, C₆₋₁₀ aryl, orC₃₋₉ heteroaryl. The reagent may be formed, for example, by the reactionof an alcohol HOR¹³ with allylation reagent 3 in the presence of a base.The base may be an amine, such as, for example, triethylamine. Exemplaryallylation reagents containing an alkoxy group include reagents wherethe alkoxy group OR¹³ is methoxy, isopropoxy, or butoxy. For example,the reaction of allylation reagent 25, in which OR¹³ is isopropoxy, with3-phenylpropanal gives the homoallylic alcohol with 94% ee, as shown inScheme 7:

In another embodiment of the invention, a compound of formula

is formed by reacting a reagent of formula (4)

with a compound of formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹. In the compound offormula R¹²C(R¹⁴)═N—X₄—CO—R¹¹, R¹² may be, for example, methyl, t-butyl,phenyl, 2-phenylethyl, (E)-2-phenylethenyl, benzyloxymethyl, cyclohexyl,iso-butyl, or tributylsilyloxymethyl. In the same compound, R¹¹ and R¹⁴may be, for example, hydrogen methyl, t-butyl, phenyl, 2-phenylethyl,(E)-2-phenylethenyl, benzyloxymethyl, cyclohexyl, iso-butyl, ortributylsilyloxymethyl.

The reagent may be an allylation reagent (X₃═C(R⁴)(R⁵)). For example,the reaction of the (S,S)-allylation reagent 26 with Ph-CH═N—NH—CO—CH₃gives compound 27 in 98% ee and 80% yield, as shown in Scheme 8:

may be a reagent in which X₃═O. This reagent may be prepared by reactinga second reagent having formula

with one equivalent of a lithium enolate of the formulaLi—O—C(R³)═C(R¹)(R²). The second reagent may in turn be prepared by acompound having formula (3) with a silane having the formula SiCl₃R⁶,which may be, for example, tetrachlorosilane.

The reagent having formula (5)

may react with an aldehyde R¹⁰—CHO to form a compound having formula

The reaction may be performed under similar conditions to those used forthe reaction of R¹⁰—CHO with an allylation reagent.

Similarly, the reagent having formula (5)

may react with a compound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ to form acompound having formula

The reaction may be performed under similar conditions to those used forthe reaction of a compound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ with anallylation reagent.

In another embodiment of the invention, a reagent having formula (18)

is reacted with an aldehyde to give a diol. Without wishing to be boundby any theory or mechanism, it is believed that the formation of thediol takes place according to Scheme 9, in which the enol terminalcarbon attacks the aldehyde to form aldol addition intermediate A, whichfurther undergoes a diastereoselective intramolecular allylation to givea diol having two chiral centers.

The reagent may be, for example, an allylation reagent containing anenol group and having formula

which may be formed by reacting (R⁷)(R⁸)C═C(R⁹)OLi with an allylationreagent of formula (12)

where R⁶ is halogen or —OSO₂CF₃. As an example, the substituents R⁷, R⁸and R⁹ may each be independently hydrogen, methyl, or phenyl.

The allylation reagent containing an enol group may be formed bytreating allylation reagent 1 with a lithium enolate, which may begenerated, for example, by treatment of a vinyltrimethoxysilane of theformula R⁷R⁸C═CR⁹OSiMe₃ with methyllithium in ether. For example,treatment of H₂C═CHOSiMe₃ with methyllithium in ether gives acetaldehydelithium enolate, which reacts with reagent 1 to give allylenolsilanereagent 11 with 72% yield, as shown in Scheme 10. Reagent 11 may bedistilled to purity, and has a shelf-life of at least several weekswithout noticeable decomposition.

When treated with benzaldehyde in benzene at 50° C. for 8 hours, reagent11 reacted to form diol 12 with 66% yield as an 8:1 syn:anti mixture ofdiastereomers. The direct allylation product 2 was also obtained with13% yield. The reaction of 11 with cyclohexanecarboxaldehyde for 13hours gave diol 13 with 56% yield as a 10:1 syn:anti mixture ofdiastereomers. The allylation product 7 was also obtained with 15%yield, as shown in Scheme 10. The allylation reagent may be reacted withthe aldehyde R¹⁰CHO to give a diol in a solvent, which may be, forexample, toluene, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate,dichloromethane, hexane, t-butyl methyl ether, diethyl ether,acrylonitrile, or benzene. In an exemplary embodiment, the concentrationof the aldehyde in the solvent may range from 0.05 M to 0.5 M. Forexample, a concentration of about 0.2 M aldehyde may be used. In anotherexemplary embodiment, the reaction may be performed in the absence ofsolvent. Exemplary aldehydes include aldehydes where Rio is methyl,t-butyl, phenyl, 2-phenylethyl, (E)-2-phenylethenyl, benzyloxymethyl,cyclohexyl, iso-butyl, or tributylsilyloxymethyl.

As another example, trans-crotylenolsilane 14 reacted withcyclohexanecarboxaldehyde according to the equation shown in Scheme 11to form diol 15, in which 3 new chiral centers are created, in 45% yieldand >10:1 diastereoselectivity. No crotylation product analogous to 7was obtained (see Scheme 10). Without wishing to be bound by anymechanism or theory, it is believed that the trans-disposed methyl groupof 14 slows the rate of transfer of the crotyl group, and that thereforeno crotyl group transfer occurs until after the formation of an aldoladdition intermediate, in accordance with Scheme 9.

As another example, shown in Scheme 11, allyl-cis-enolsilane 16 reactedwith cyclohexanecarboxaldehyde to give a 10:3:1 mixture of diastereomerswith 60% yield. Diol 17 was shown to be the major diastereomer.

An allylation reagent containing an enol group may also be formed, forexample, by treating allylation reagent 29, formed from the reaction ofchiral diol 28 with allyltrichlorosilane as previously discussed, inconnection with equation (I), with a lithium enolate. For example,allylation reagent 30 may be formed as shown in Scheme 12. Whenallylation reagent 30 is reacted with benzaldehyde, the correspondingdiol is formed in 70% yield and 68% ee.

The reagent which reacts with an aldehyde to give a diol may be areagent containing two enol groups and having formula (15)

In one embodiment of the invention, the group C(R⁹)═C(R⁸)(R⁷) isidentical to the group C(R³)═C(R¹)(R²). In this embodiment, the reagentmay be formed by reacting a second reagent of the formula (6)

with two equivalents of a lithium enolate of the formulaLi—)—C(R³)═C(R¹)(R²), or by reacting a third reagent of formula (5)

where R⁶ is a halogen or —OSO₂CF₃, with one equivalent of a lithiumenolate of formula Li—O—C(R³)═C(R¹)(R²). The reagent containing two enolgroups may react with an aldehyde R¹⁰—CHO to form a diol under similarconditions to those used for the reaction of R¹⁰—CHO with an allylationreagent containing an enol group.

In another embodiment, a compound of formula (19)

is formed by reacting a reagent of formula (20)

with a compound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ to form thecompound of formula (19).

The reagent of formula (20)

may be an allylation reagent containing an enol group (X₃═C(R⁴)(R⁵)) ora reagent containing two enol groups (X₃═O). In an exemplary embodimentwhere X₃═O, the two enol groups O—C(R⁹)═C(R⁸)(R⁷) and O—C(R³)═C(R¹)(R²)are identical. The reagent may be reacted with the compound of theformula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ in a solvent such as toluene,tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, dichloromethane,hexane, t-butyl methyl ether, diethyl ether, acrylonitrile, or benzene.In an exemplary embodiment, the concentration of the compound of theformula R¹²C(R⁴)═N—X₄—CO—R¹¹ in the solvent may range from 0.05 M to 0.5M. For example, a concentration of about 0.2 M of compound of theformula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ may be used. In another exemplaryembodiment, the reaction may be performed in the absence of solvent.Examples of the compound of the formula R¹²C(R¹⁴)═N—X₄—CO—R¹¹ includecompounds where R¹² is methyl, t-butyl, phenyl, 2-phenylethyl,(E)-2-phenylethenyl, benzyloxymethyl, cyclohexyl, iso-butyl, ortributylsilyloxymethyl, and each of R¹¹ and R¹⁴ is independentlyhydrogen, methyl, t-butyl, phenyl, 2-phenylethyl, (E)-2-phenylethenyl,benzyloxymethyl, cyclohexyl, iso-butyl, or tributylsilyloxymethyl.

The invention may be further described by the following examples, whichare illustrative of the invention but which are not intended to definethe scope of the invention in any way.

EXAMPLES

Preparation of(4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine:To a cooled (0° C.) solution of allyltrichlorosilane (101 mL, 0.696 mol)in methylene chloride (1.8 L) under argon was added triethylamine (170mL, 1.21 mol). (1S,2S)-pseudoephedrine (100 g, 0.605 mol) was then addedportionwise over 30 min, to maintain internal temperature below 15° C.After the addition was complete the mixture was stirred for 12 hours atambient temperature. The methylene chloride was removed by distillationand the residue was diluted with pentane (1.5 L). The mixture wasvigorously stirred for 12 hours to ensure complete precipitation of thetriethylamine salts. Filtration of the resulting suspension through apad of celite and concentration of the filtrate by distillation affordedthe crude product as a pale yellow oil. Purification by distillationunder reduced pressure (bp˜120 C, 5 mm Hg) provided 149 g (92%) of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a˜2:1 mixture of diastereomers.

Preparation of(4R,5R)-2-(cis)-but-2-enyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine:To a cooled (0° C.) solution of cis-but-2-enyl-trichlorosilane (7.0 g,37 mmol) in methylene chloride (80 mL) was added triethylamine (8.75 mL,63 mmol). (1R,2R)-psuedoephedrine (5.20 g, 31 mmol) was addedportionwise and the mixture was allowed to stir for 12 hours. Themethylene chloride was removed by distillation and pentane (50 mL) wasadded to the residue. The mixture was allowed to stir for 1 hour toensure complete precipitation of the triethylamine salts. The suspensionwas filtered through a pad of celite. The filtrate was concentrated togive a pale yellow oil which was distilled under reduced pressure togive 5.85 g (68%) of(4R,5R)-2-(cis)-but-2-enyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidineas a ˜2.4:1 mixture of diastereomers.

Preparation of(4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine:To a solution of(4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine(2.08 g, 7.8 mmol) in methylene chloride (25 mL) was added triethylamine(1.2 mL, 8.6 mmol). 2-Propanol (0.6 mL, 7.8 mmol) was added slowly bysyringe and the mixture was allowed to stir for 12 hours. The methylenechloride was removed by distillation and pentane (20 ml) was added tothe residue. The mixture was stirred for 3 hours. The mixture was thenfiltered through a pad of celite. The filtrate was concentrated toafford an oil which was distilled under reduced pressure (b.p. ˜72° C.,˜0.2 mm Hg) to yield 1.08 g (48%) of(4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidineas a ˜2:1 mixture of diastereomers.

Preparation of(4R,5R)-2-Allyl-1,3-bis-(4-bromo-benzyl)-2-chloro-octahydro-benzo[1,3,2]diazasilole:To a cooled (0° C.) solution of allyltrichlorosilane (2.05 ml, 14.1mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.24 ml, 28.4 mmol) indichloromethane (50 ml) was added(R,R)-N,N′-bis-(4-bromo-benzyl)-cyclohexane-1,2-diamine (5.37 g, 11.9mmol) in dichloromethane (20 ml) over 50 min. After 2 h, the mixture waswarmed to room temperature, and was stirred for 13 h. The reactionmixture was concentrated. Diethylether (60 ml) was added, and themixture was stirred for 1 h. The mixture was filtrated through a pad ofcelite with ether washes (2×10 ml). The filtrate was concentrated.Benzene (10 ml) was added, and the solution was concentrated. Thisprocedure was repeated and upon standing in a freezer, the resulting oilsolidified to give 5.37 g (88%) of (4R,5R)-2-Allyl-1,3-bis-(4-bromo-benzyl)-2-chloro-octahydro-benzo[1,3,2]diazasiloleas a white solid.

Enantioselective allylation of dihydrocinnamaldehyde to give(3R)-1-phenyl-hex-5-en-3-ol: To a cooled (−10° C.) solution of(4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine(380 mg, 1.5 mmol) in toluene (5 mL) was added dihydrocinnamaldehyde(1.0 mmol). The reaction mixture was maintained at −10° C. for 2 h. Tothis cooled solution was added 1N HCl (4 mL) and EtOAc (4 mL) and themixture was vigorously stirred for 15 min. The layers were separated andthe aqueous layer was extracted with EtOAc (2×5 mL). The combinedorganics were dried (MgSO₄), filtered, and concentrated. The residue waspurified by flash chromatography on silica gel to give(3R)-1-phenyl-hex-5-en-3-ol in 84% yield and 88% enantiomeric excess(ee).

Enantioselective crotylation of dihydrocinnamaldehyde to give(3S,4S)-4-Methyl-1-phenyl-hex-5-en-3-ol: To a cooled (−10° C.) solutionof(4R,5R)-2-((cis)-but-2-enyl)-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine(0.431 g, 1.5 mmol) in toluene (2.5 mL) was added dihydrocinnamaldehyde(0.132 mL, 1.0 mmol). The reaction mixture was allowed to stir for 12hours at −10° C. To this solution was added 1N HCl (4 mL) and EtOAc (4mL) and the mixture was stirred for 10 min. The layers were separatedand the aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganics were dried over MgSO₄, filtered, and concentrated. HPLCanalysis of the residue at this stage revealed a syn:antidiastereoselectivity of 10:1, and an enantiomeric excess for the majorsyn product of 81%. The residue was purified by chromatography on silicagel to afford 0.116 g (61%) of (3S,4S)-4-Methyl-1-phenyl-hex-5-en-3-ol(81% ee).

Enantioselective allylation of dihydrocinnamaldehyde to give(3R)-1-phenyl-hex-5-en-3-ol: To a solution of(4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine(0.437 g, 1.5 mmol) in toluene (2.5 mL) was added dihydrocinnamaldehyde(0.132 mL, 1.0 mmol). The mixture was allowed to stir at ambienttemperature (˜21° C.) for 18 hours. To this solution was added 1N HCl (4mL) and EtOAc (4 mL) and the mixture was stirred for 10 min. The layerswere separated and the aqueous layer was extracted with EtOAc (3×5 mL).The combined organics were dried over MgSO₄, filtered, and concentrated.The residue was purified by chromatography on silica gel (5%EtOAc/hexanes) to afford 0.119 g (69%) of (3R)-1-phenyl-hex-5-en-3-ol in94% enantiomeric excess (ee).

Enantioselective allylation of 3-benzyloxypropionaldehyde to give(3S)-1-benzyloxy-hex-5-en-3-ol: To a cooled (−10° C.) solutionof(4R,5R)-2-Allyl-1,3-bis-(4-bromo-benzyl)-2-chloro-octahydro-benzo[1,3,2]diazasilole(1.0 mmol) in CH₂Cl₂ (5 mL) was added 3-benzyloxypropionaldehyde (1.0mmol). The reaction mixture was transferred to a freezer (−10° C.) andmaintained at that temperature for 20 h. To this cooled solution wasadded 1N HCl and EtOAc, and the mixture was vigorously stirred at roomtemperature for 15 min. The layers were separated and the aqueous layerwas extracted with EtOAc 3 times. The combined organic layers werediluted with hexane, dried (MgSO₄), filtered, and concentrated.Purification of the residue by chromatography on silica gel gave(3S)-1-benzyloxy-hex-5-en-3-ol in 87% yield and 98% ee.

Enantioselective allylation of acetic acid benzylidene-hydrazide (8) togive (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide: To a cooled(10° C.) solution of(4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine(9.90 g, 37.0 mmol) in CH₂Cl₂ (300 mL) was added acetic acidbenzylidene-hydrazide (5.00 g, 30.8 mol) as a solid. The resultingsolution was stirred for 16 hours and methanol (40 mL) was then added.After 15 min all volatiles were removed by distillation and the residuewas diluted with EtOAc (150 mL) and H₂O (500 mL). The phases wereseparated and the aqueous layer was extracted with EtOAc (2×150 mL). Thecombined organic layers were washed with H₂0 and brine, dried (MgSO₄),filtered and concentrated. Analysis of the residue by HPLC revealed anee of 87%. The residue was dissolved in boiling toluene (80 mL) and thesolution was then cooled to ambient temperature. Pentane (380 mL) waslayered on top of the toluene solution and the resulting biphasicsolution was allowed to stand for 16 hours. The resulting crystallinesolid precipitate was filtered, washed (pentane:toluene (5:1)) and thendried in vacuo to give 5.04 g (80%) of (1R)-acetic acidN′-(1-phenyl-but-3-enyl)-hydrazide in 98% ee.

Preparation of 2-allyl-2-chloro-4,4,55-tetramethyl-[1,3,2]dioxasilolane: To a cooled (0° C.) solution ofallyltrichlorosilane (4.9 mL; 34 mmol) in CH₂Cl₂ (50 mL) was added1,8-Diazabicyclo[5.4.0]undec-7-ene (13 mL; 84 mmol). A solution ofpinacol (4.0 g; 34 mmol) in CH₂Cl₂ (50 mL) was then added slowly and theresultant solution was warmed to room temperature and stirred for 12hours. The solution was concentrated and the residue was treated withdiethylether (100 mL). The mixture was stirred for 1 hour during whichtime the formation of a precipitate was observed. The mixture was thenfiltered and the filtrate was concentrated. The residue was distilledunder reduced pressure to give 5.2 g (72%) of2-allyl-2-chloro-4,4,5,5-tetramethyl-[1,3,2]dioxasilolane as a clear,colorless liquid.

Preparation of2-allyl-4,4,5,5-tetramethyl-2-vinyloxy-[1,3,2]dioxasilolane: To a cooled(0° C.) solution of MeLi (16.2 mL; 23 mmol; 1.4 M in Et₂0) was addedtrimethylvinyloxysilane (2.7 g; 23 mmol). The solution was warmed toroom temperature and was stirred for 1 hour. The solution was cooled to−78° C., and 2-allyl-2-chloro-4,4,5,5-tetramethyl-[1,3,2]dioxasilolane(5.5 g; 25 mmol) was added. The solution was warmed to room temperatureand stirred for 2 hours. The solution was diluted with pentane (20 mL),and the mixture was then filtered through a pad of celite. The filtratewas concentrated, and the residue was distilled under reduced pressureto give 3.8 g (70%) of2-allyl-4,4,5,5-tetramethyl-2-vinyloxy-[1,3,2]dioxasilolane as a clear,colorless liquid.

Tandem aldol-allylation reaction of cyclohexanecarboxaldehyde to give(syn)-1-cyclohexyl-hex-5-ene-1,3-diol: To a solution of2-allyl-4,4,5,5-tetramethyl-2-vinyloxy-[1,3,2]dioxasilolane (0.63 mmol)in toluene (0.4 mL) was added cyclohexanecarboxaldehyde (48 mg; 0.42mmol). The solution was heated to 40° C. and stirred at that temperaturefor 24 h. The solution was cooled and 1 M HCl (5 mL) was added followedby ethyl acetate (5 mL). The mixture was stirred for 20 min and thelayers were separated. The organic layer was washed with saturatedaqueous NaHCO₃ (5 mL), washed with brine (5 mL), dried (Na₂SO₄),filtered, and concentrated. The residue was purified by chromatographyon silica gel to give racemic (syn)-1-cycloliexyl-hex-5-ene-1,3-diol in59% yield.

Tandem aldol-allylation reaction of cyclohexanecarboxaldehyde to give(syn,anti,syn)-1-cyclohexyl-2,4-dimethyl-hex-5-ene-1,3-diol: To asolution of(trans,trans)-2-but-2-enyl-4,4,5,5-tetramethyl-2-propenyloxy-[1,3,2]dioxasilolane(prepared by an exactly analogous procedure to that used for thepreparation of2-allyl-4,4,5,5-tetramethyl-2-vinyloxy-[1,3,2]dioxasilolane) (0.63 mmol)in benzene (0.4 mL) was added cyclohexanecarboxaldehyde (48 mg; 0.42mmol). The solution was heated to 40° C. and stirred at that temperaturefor 132 h. The solution was cooled and 1 M HCl (5 mL) was added followedby ethyl acetate (5 mL). The mixture was stirred for 20 min and thelayers were separated. The organic layer was washed with saturatedaqueous NaHCO₃ (5 mL), washed with brine (5 mL), dried (Na₂SO₄),filtered, and concentrated. ¹H NMR analysis at this stage revealed thepresence of 4 diastereomeric products in a 86:11:3:1 ratio. The majorproduct was isolated by chromatography on silica gel to give racemic(syn,anti,syn)-1-cyclohexyl-2,4-dimethyl-hex-5-ene-1,3-diol in 60%yield.

Preparation of(4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-[1,3,2]dioxasilolane:To a cooled (0° C.) solution of allyltrichlorosilane (7.0 mL; 48 mmol)in CH₂Cl₂ (80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15 mL;102 mmol). A solution of(3R,4R)-2,5-dimethoxy-2,5-dimethyl-hexane-3,4-diol (10.0 g; 48 mmol) inCH₂Cl₂ (80 mL) was then added and the mixture was allowed to warm toambient temperature and stirred for 12 hours. The solution wasconcentrated and the residue was treated with diethylether (100 mL). Themixture was stirred for 1 hour. The mixture was then filtered and thefiltrate was concentrated. The residue was distilled under reducedpressure to give 6.6 g (44%) of(4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolaneas a clear, colorless liquid.

Preparation of(4R,5R)-2-allyl-2-isopropenyloxy-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane:To a cooled (0° C.) solution of MeLi (13.0 mL; 21 mmol; 1.6 M in Et₂O)was added 2-(trimethylsilyloxy)propene (2.8 g; 21 mmol). The solutionwas stirred 30 minutes at 0° C., and then warmed to room temperature andwas stirred for 1 hour. The mixture was recooled to 0° C., and(4R,5R)-2-allyl-2-chloro-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane(6.6 g; 21 mmol) was added. The mixture was warmed to room temperatureand stirred for 2 hours. The solution was diluted with pentane (20 mL),and the mixture was then filtered through a pad of celite. The filtratewas concentrated, and the residue was distilled under reduced pressureto give 3.0 g (43%) of(4R,5R)-2-allyl-2-isopropenyloxy-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolaneas a clear, colorless liquid.

Asymmetric tandem aldol-allylation reaction of benzaldehyde to give(1S,3S)-3-methyl-1-phenyl-hex-5-ene-1,3-diol: To a solution of(4R,5R)-2-allyl-2-isopropenyloxy-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3,2]dioxasilolane(0.75 mmol) in benzene (0.3 mL) was added benzaldehyde (0.50 mmol). Themixture was heated to 40° C. (oil bath) and stirred at that temperaturefor 48 hours. The solution was cooled and 1 M HCl (10 mL) was addedfollowed by ethyl acetate (10 mL). The mixture was stirred for 20 min.The layers were separated and the aqueous layer was extracted with ethylacetate (10 mL). The combined organic layers were washed with saturatedaqueous NaHC0₃ (10 mL) and brine (10 mL), dried (Na₂SO₄), filtered, andconcentrated. Analysis of the residue by HPLC and ¹H NMR revealed a5.5:1 mixture of diastereomers and an enantiomeric excess for the majorproduct of 68%. The residue was purified by chromatography on silica gelto give (1S,3S)-3-methyl-1-phenyl-hex-5-ene-1,3-diol in 70% yield and in68% ee.

Determination of Enantioselectivity and Absolute Configuration ofHomoallylic Alcohol Products:

Allylation of Benzaldehyde with allylation reagent 3: The ee wasdetermined by chiral HPLC analysis using a chiralcel OD column, as shownin FIG. 3. The (R) enantiomer elutes first.

Allylation of Cinnamaldehyde with allylation reagent 3: The ee wasdetermined by chiral HPLC analysis using a chiralcel OD column, as shownin FIG. 4. The (R) enantiomer elutes first.

Allylation of Dihydrocinnamaldehyde with allylation reagent 3: The eewas determined by chiral HPLC analysis using a chiralcel OD column, asshown in FIG. 5. The (S) enantiomer elutes first.

Allylation of Isovaleraldehyde with allylation reagent 3: The ee wasdetermined by ¹⁹F NMR (C₆D₆, 282 MHz) analysis of the Mosher ester ofthe product, as shown in FIG. 6. The absolute configuration (R) of thealcohol product was determined by optical rotation and comparison to theliterature value: [α]_(D) ²⁰+18.2° (CH₂Cl₂, c 0.74); literature: [α]_(D)²⁰−2.5° (CH₂Cl₂, c 9.26) for the (S) enantiomer of 16% ee.

Allylation of Cyclohexanecarboxaldehyde with allylation reagent 3: Theee was determined by ¹⁹F NMR (C₆D₆, 282 MHz) analysis of the Mosherester of the product, as shown in FIG. 7. The absolute configuration (S)of the alcohol product was determined by optical rotation and comparisonto the literature value: [α]_(D) ²⁰−6.67° (EtOH, c 0.775); lit: [α]_(D)²⁴+9.7° (EtOH, c 1.00) for the (R) enantiomer of 98% ee.

Allylation of Pivaldehyde with allylation reagent 3: The ee wasdetermined by ¹⁹F NMR (C₆D₆, 282 MHz) analysis of the Mosher ester ofthe product, as shown in FIG. 8. The absolute configuration (S) of thealcohol product was determined by optical rotation and comparison to theliterature value: [α]_(D) ²⁰−13.2° (PhH, c 0.28); lit: [α]_(D)+10.3°(PhH, c 10.5) for the (R) enantiomer of 88% ee.

Allylation of Benzyloxyacetaldehyde with allylation reagent 3: The eewas determined by ¹⁹F NMR (C₆D₆, 282 MHz) analysis of the Mosher esterof the product, as shown in FIG. 9. The absolute configuration (S) ofthe alcohol product was determined by optical rotation and comparison tothe literature value: [α]_(D) ¹⁸+5.77° (CHCl₃, c 1.06); lit: [α]_(D)²⁵−6.6° (CHCl₃, c 2.1) for the (R) enantiomer of >99% ee.

Allylation of tert-Butyldimethylsilyloxyacetaldehyde with allylationreagent 3: The ee was determined by ¹⁹F NMR (C₆D₆, 282 MHz) analysis ofthe Mosher ester of the product, as shown in FIG. 10. The absoluteconfiguration (S) of the alcohol product was determined by opticalrotation and comparison to the literature value: [α]_(D) ²⁰+1.4° (CHCl₃,c 1.00); lit: [α]_(D) ²⁰+1.7° (CHCl₃, c 0.24) for the (S) enantiomer of59% ee.

Allylation of 3-(Benzyloxy)pronionaldehyde with allylation reagent(R,R)-21: The ee was determined by chiral HPLC analysis using achiralcel OD column, as shown in FIG. 12.

Allylation of p-Anisaldehyde with allylation reagent (R,R)-21: The eewas determined by chiral HPLC analysis using a chiralcel OD column, asshown in FIG. 13. The (R) enantiomer elutes first.

Allylation of p-CF₃-Benzaldehyde with allylation reagent (R,R)-21: Theee was determined by chiral HPLC analysis using a chiralcel OJ-H column,as shown in FIG. 14. The (S) enantiomer elutes first.

Allylation of trans-2-Hexenal with allylation reagent (R,R)-21: The eewas determined by chiral HPLC analysis of the derived benzoate using achiralcel AD-H column, as shown in FIG. 15.

Determination of Enantioselectivity and Absolute Configuration ofProducts of Tandem Aldol Allylation Reactions ofCyclohexanecarboxaldehyde:

The diol having the formula

was treated with 2,2-dimethoxypropane and a catalytic amount of(+)-camphorsulfonic acid (CSA) in CH₂Cl₂ to give acetonide A (equationXVIII). The ¹³C NMR spectrum of acetonide A was analyzed to reveal thatthe acetonide possessed the syn relative configuration, establishing thesyn stereochemistry of the diol.

Spectroscopic data for acetonide A: ¹H NMR (400 MHz, CDCl₃) δ 5.85-5.72(m, 1H, CH═CH₂), 5.10-4.99 (m, 2H, CH═CH₂), 3.85-3.77 (m, 1H, CH),3.52-3.45 (m, 1H, CH), 2.33-2.24 (m, 1H, one of CH₂), 2.17-2.08 (m, 1H,one of CH₂), 1.92-1.83 (m, 1H, one of CH₂), 1.74-1.58 (m, 4H, one of CH₂and three of C₆H₁₁), 1.51-0.81 (m, 8H, eight of C₆H₁₁), 1.38 (s, 3H,CH₃) 1.36 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 134.4, 116.9, 98.3,73.2, 68.8, 42.8, 41.0, 33.4, 30.2, 28.9, 27.9, 26.6, 26.1, 25.9, 19.8;IR (thin film) 3077, 2992, 2925, 2853, 1643, 1451, 1379, 1262, 1200,1171 cm⁻¹.

The diol having the formula

was treated with 2,2-dimethoxypropane and a catalytic amount of(+)-camphorsulfonic acid in CH₂Cl₂ to give acetonide B (equation XIX).The ¹³C NMR spectrum of this acetonide was analyzed to reveal that theacetonide possessed the syn relative configuration, establishing the synstereochemistry of the diol. The relative configuration of the allylicmethyl group was deduced from the sterochemistry of acetonide D, whichwas assigned as described below.

Spectroscopic data for acetonide B: ¹H NMR (300 MHz, CDCl₃) δ 5.73-5.60(m, 1H, CH═CH₂), 5.00-4.91 (m, 2H, CH═CH₂), 3.50-3.37 (m, 2H, twoCHOC(CH₃)₂, 2.17-2.05 (m, 1H, CH(CH₃)CH═CH₂), 1.85-1.00 (br m, 13H, CH₂and C₆H₁₁), 1.31 (s, 3H, one of CH₃), 1.30 (s, 3H, one of CH₃), 0.95 (d,J=6.7 Hz, 3H, CH(CH₃)CH═CH₂); ¹³C NMR (75 MHz, CDCl₃) δ 140.4, 114.7,98.2, 73.3, 72.5, 43.5, 42.9, 31.5, 30.2, 28.9, 28.0, 26.6, 26.1, 26.0,19.7, 15.7; IR (thin film) 3078, 2921, 2852, 1636, 1450, 1376, 1259,1200, 1106 cm⁻¹.

The diol having the formula

was treated with 2,2-dimethoxypropane and a catalytic amount of(+)-camphorsulfonic acid in CH₂Cl₂ to give acetonide C (equation XX).The ¹³C NMR spectrum of this acetonide was analyzed to reveal that theacetonide possessed the syn relative configuration, establishing the synstereochemistry of the diol. The relative configuration of the allylicmethyl group was assigned as described below.

Spectroscopic data for acetonide C: ¹H NMR (300 MHz, CDCl₃) δ 5.90-5.78(m, 1H, CH═CH₂), 5.04-4.98 (m, 2H, CH═CH₂), 3.70-3.64 (m, 1H, one ofCHOC(CH₃)₂), 3.52-3.45 (m, 1H, one of CHOC(CH₃)₂), 2.24-2.20 (m, 1H,CH(CH₃)CH═CH₂), 1.93-0.88 (m, 13H, C₆H₁₁ and CH₂), 1.38 (s, 3H, one ofCH₃), 1.36 (s, 3H, one of CH₃), 1.00 (d, J=6.9 Hz, 3H, CH(CH₃)CH═CH₂);¹³C NMR (75 MHz, CDCl₃); δ 140.6, 114.2, 98.0, 73.1, 72.4, 42.8, 42.4,30.4, 30.0, 28.8, 28.0, 26.6, 26.0, 25.9, 19.6, 14.8; IR (thin film)3078, 2921, 2852, 1636, 1450, 1376, 1259, 1200, 1106cm⁻¹.

Acetonide C was subjected to ozonolysis with a reductive workup withNaBH₄, and the resulting alcohol was treated with PPTS in CH₂Cl₂ to giveacetonide D (equation XXI). Analysis of the coupling constants of D inthe ¹H NMR spectrum established the anti relative configuration of theallylic methyl group. Since acetonides B and D were both shown to havethe syn diol stereochemistry and since they are different compounds, thesyn relative configuration of the allylic methyl group in B and in thediol starting material is also thereby proven.

Spectroscopic data for acetonide D: ¹H NMR (300 MHz, acetone-d₆) δ3.75-3.67 (m, 1H, CHOC(CH₃)₂ or CHOH), 3.57 (dd, J=5.4, 11.6 Hz, 1H, oneof CH₂OC(CH₃)₂), 3.48 (dd, J=11.0, 11.0 Hz, 1H, one of CH₂OC(CH₃)₂),3.50-3.45 (m, 1H, CHOC(CH₃)₂ or CHOH), 3.36 (br s, 1H, OH), 1.83-0.98(m, 14H, C₆H11, CH₂, and CHCH₃), 1.41 (s, 3H, one of CH₃), 1.25 (s, 3H,one of CH₃), 0.72 (d, J=6.7 Hz, 3H, CH(CH₃)); ¹³C NMR (100 MHz, CDCl₃) δ98.2, 77.6, 76.4, 65.8, 43.9, 36.4, 34.5, 29.7, 28.9, 27.8, 26.6, 26.3,26.2, 19.2, 12.6; IR (thin film) 3522, 2925, 1450, 1377, 1264, 1200,1111 cm⁻¹.

The diol having the formula

was treated with 2,2-dimethoxypropane and a catalytic amount of(+)-camphorsulfonic acid in CH₂Cl₂ to give acetonide E (equation XXII).The ¹³C NMR spectrum of this acetonide was analyzed to reveal that theacetonide possessed the syn relative configuration, establishing the synstereochemistry of the diol. Analysis of the coupling constants of E,obtained from decoupling experiments, in the ¹H NMR spectrum establishedthe anti relative configuration of the methyl group.

Spectroscopic data for acetonide E: ¹H NMR (400 MHz, CDCl₃) δ 5.86-5.96(m, 1H, CH═CH_(Z)), 5.01-5.08 (m, 2H, CH═CH₂), 3.50 (m, 1H, OCHCH₂),3.28 (d, 1H, J=10.3 Hz, c-C₆H₁₁CHO), 2.34-2.41 (m, 1H, one ofCH₂CH═CH₂), 2.13-2.21 (m, 1H, one of CH₂CH═CH₂), 1.71-1.77 (m, 2H, twoof c-C₆H₁₁), 1.37 (s, 3H, three of C(CH₃)₂), 1.34 (s, 3H, three ofC(CH₃)₂), 1.11-1.65 (m, 10H, CHCH₃ and nine of c-C6H₁₁), 0.74 (d, 3H,J=6.6 Hz, CHCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 135.3, 116.1, 97.7, 77.7,74.2, 38.4, 37.6, 34.2, 30.4, 30.1, 26.9, 26.6, 26.5, 24.8, 19.5, 11.8;IR (film) 3075, 2991, 2931, 2853, 1641, 1451, 1379, 1264, 1203, 1176,1131, 1051, 1015, 987, 935, 910 cm⁻¹.

The diol having the formula

was treated with 2,2-dimethoxypropane and a catalytic amount of(+)-camphorsulfonic acid in CH₂Cl₂ to give acetonide F (equation XXIII).The ¹³C NMR spectrum of this acetonide was analyzed to reveal that theacetonide possessed the syn relative configuration, establishing the synstereochemistry of the diol. Analysis of the coupling constants in the¹H NMR spectrum established the anti relative configuration of themethyl group between the two OH groups.

Spectroscopic data for acetonide F: ¹H NMR (400 MHz, CDCl₃) δ 5.96-5.82(m, 1H, CH═CH₂), 5.07-4.94 (m, 2H, CH═CH₂), 3.35 (dd, J=10.1, 1.7 Hz,1H, CHO), 3.28 (d, J=10.8 Hz, 1H, CHO), 2.51-2.39 (m, 1H, CH), 1.84-1.12(m, 12H, CH and C₆H₁₁), 1.37 (s, 3H, CH₃), 1.34 (s, 3H, CH₃), 1.07 (d,J=6.9 Hz, 3H, CHCH₃), 0.72 (d, J=6.6 Hz, 3H, CHCH₃); ¹³C NMR (100 MHz,CDCl₃) δ 140.1, 114.5, 97.5, 77.8, 77.6, 39.6, 38.5, 32.4, 30.5, 30.1,26.9, 26.6, 24.9, 19.3, 18.1 11.2; IR (thin film) 3072, 2990, 2930,2853, 1642, 1451, 1378, 1256, 1202, 1176 cm⁻¹.

To establish the relative configuration of the allylic methyl group ofthe diol, the diol was first converted to a mixture of benzyl etherswhich was treated with Hg(OAc)Cl in acetone to give terahydropyran G(equation XXIV) along with other products. Analysis of the couplingconstants and NOE studies established the stereochemistry of the allylicmethyl group of the diol.

Spectroscopic data for tetrahydropyran G: ¹H NMR (400 MHz, CDCl3) δ7.42-7.28 (m, 5H, C₆H₅), 4.69-4.61 (m, 2H, PhCH₂), 3.80 (ddd, J=9.8,7.6, 4.7 Hz, 1H, CH), 3.52-3.44 (m, 2H, two CH), 2.35 (dd, J=11.7, 4.7Hz, 1H, one of CH₂HgCl), 2.08 (dd, J=11.7, 7.6 Hz, 1H, one of CH₂HgCl),1.85-1.13 (m, 13H, two CH and C6H₁₁), 1.00 (d, J=6.9 Hz, 3H, CHCH₃),0.95 (d, J=7.0 Hz, CHCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 139.0, 128.2,127.4, 127.2, 83.4, 80.4, 75.8, 75.7, 46.1, 38.2, 38.0, 37.9, 30.9,26.9, 26.6, 24.6, 14.5, 13.8; IR (KBr) 3025, 2930, 2855, 1654, 1607,1450, 1376, 1337, 1193, 1095, 1067 cm⁻¹.

The diol having the formula

was treated with 2,2-dimethoxypropane and a catalytic amount of(+)-camphorsulfonic acid in CH₂Cl₂ to give acetonide H (equation XXV).The ¹³C NMR spectrum of this acetonide was analyzed to reveal that theacetonide possessed the syn relative configuration, establishing the synstereochemistry of the diol. Analysis of the coupling constants in the¹H NMR spectrum established the anti relativeconfiguration of the methyl group between the two OH groups. Since theanti allylic methyl group stereocenter of acetonide F has beenestablished, and since the diol starting materials corresponding toacetonides F and H differ only in the allylic methyl groupstereochemistry, the syn orientation of the allylic methyl group inacetonide H and in the corresponding diol starting material is thereforeestablished.

Spectroscopic data for acetonide H: ¹H NMR (400 MHz, CDCl₃) δ 6.00-5.89(m, 1H, CH═CH₂), 5.06-4.95 (m, 2H, CH═CH₂), 3.47 (dd, J=10.1, 2.4 Hz,1H, CH), 3.30 (dd, J=10.1, 1.2 Hz, 1H, CH), 2.46-2.37 (m, 1H, CH),1.83-1.11 (m, 12H, CH and C6H₁₁), 1.36 (s, 3H, CH₃), 1.33 (s, 3H, CH₃),1.00 (d, J=6.9 Hz, 3H, CHCH₃), 0.76 (d, J=6.7 Hz, 3H, CHCH₃); ¹³C NMR(100 MHz, CDCl₃) δ 143.3, 112.8, 97.6, 77.9, 77.3, 38.6, 31.8, 30.5,30.1, 26.9, 26.6, 24.9, 19.5, 12.5, 11.5; IR (thin film) 3073, 2968,2931, 2853, 1640, 1451, 1379, 1256, 1202, 1138, 1031cm⁻¹.

The diol having the formula

was treated with HgClOAc in CH₂Cl₂/THF to give tetrahydropyran 1(equation XXVI). As illustrated, analysis of the coupling constants andselective 1D NOESY experiments unambiguously confirmed the relativestereochemistry of the diol.

Spectroscopic data for tetrahydropyran I: ¹H NMR (400 MHz, CDCl₃) δ 3.40(d, J=9.9 Hz, 1 H, CH), 3.27 (ddd, J=9.4, 8.2, 4.3 Hz, 1 H, CH), ), 3.03(dd, J=9.7, 1.8 Hz, 1H, CH), 2.39 (dd, J=11.9, 4.3 Hz, 1 H, one ofCH₂HgCl), 2.14 (dd, J=11.9, 8.2 Hz, 1H, one of CH₂HgCl), 2.16-2.07 (m,2H, two H of C₆H₁₁), 2.07-2.98 (m, 1H, CH) 1.82-1.05 (m, 8H, CH, OH, andsix H of C₆H₁₁), 0.99 (d, J=6.5 Hz, 3H, CHCH₃), 0.89 (d, J=6.9 Hz, 3H,CHCH₃), 0.94-0.75 (m, 3H, three H of C₆H₁₁); ¹³C NMR (100 MHz, CDCl₃) δ83.53, 80.4, 42.2, 38.2, 37.3, 35.9, 30.4, 28.0, 26.5, 25.9, 25.7, 13.8,5.7; IR (KBr) 3434, 2924, 2851, 1720, 1450, 1386, 1334, 1262, 1100, 1027cm⁻¹.

1. A compound having the formula

wherein X₃ is selected from a group consisting of O and C(R⁴)(R⁵); X₁and X₂ are N—R, or one of X₁ and X₂ is O and the other is N—R; each ofC_(a) and C_(b) is independently selected from the group consisting ofan achiral center, an (S) chiral center and an (R) chiral center; R_(a)and R_(b) are (i) each independently selected from a group consisting ofC₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, or (ii) taken together to forma C₃-C₄ alkylene chain which together with C_(a) and C_(b) forms a5-membered aliphatic ring and a 6-membered aliphatic ring; R_(c) andR_(d) are each independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, and C₃₋₉ heteroaryl; R⁶ is selectedfrom the group consisting of halogen, hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl,C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino, C₁₋₁₀alkyl-C₆₋₁₀ arylamino, C₆₋₁₀ diarylamino, —O—C(R⁹)═C(R⁷)(R⁸), —OSO₂CF₃and —SR; R is selected from the group consisting of C₁₋₁₀ alkyl, C₆₋₁₀aryl, and C₃₋₉ heteroaryl; and each of, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, andR⁹ is independently selected from the group consisting of hydrogen,C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy,C₁₋₁₀ dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₆₋₁₀ diarylamino, andhalogen.
 2. The compound of claim 1, wherein X₃=O.
 3. The compound ofclaim 1, wherein X₃=C(R⁴)(R⁵).
 4. The compound of claim 1, wherein eachof R¹, R², R³, R⁴, and R⁵ is hydrogen, and R⁶ is chlorine.
 5. Thecompound of claim 1, wherein the each of R_(c) and R_(d) is hydrogen,each of R_(a) and R_(b) is 2-methoxy-2-propyl, and each of C_(a) andC_(b) is an (R) chiral center.
 6. The compound of claim 1, wherein X₁=NRand X₂=O.
 7. The compound of claim 6, wherein each of C_(a) and C_(b) isan (S) chiral center.
 8. The compound of claim 6, wherein each of C_(a)and C_(b) is an (R) chiral center.
 9. The compound of claim 6, wherein Ris selected from the group consisting of methyl, benzyl and phenyl. 10.The compound of claim 9, wherein each of R_(a) and R_(b) isindependently selected from the group consisting of methyl and phenyl,and each of R_(c) and R_(d) is independently selected from the groupconsisting of methyl and hydrogen.
 11. The compound of claim 6 havingthe formula selected from a group consisting of:


12. The compound of claim 1, wherein X₁=X₂=NR.
 13. The compound of claim12, wherein each of C_(a) and C_(b) is an (S) chiral center.
 14. Thecompound of claim 12, wherein each of C_(a) and C_(b) is an (R) chiralcenter.
 15. The compound of claim 12, wherein R is selected from thegroup consisting of methyl, benzyl and phenyl.
 16. The compound of claim15, wherein each of R_(a) and R_(b) is independently selected from thegroup consisting of methyl and phenyl, and each of R_(c) and R_(d) ishydrogen.
 17. The compound of claim 12, wherein R_(a) and R_(b) aretaken together to form a C₄ alkylene chain which together with C_(a) andC_(b) forms a 6-membered aliphatic ring.
 18. The compound of claim 17having the formula selected from a group consisting of:


19. The compound of claim 1, wherein R_(c) is selected from the groupconsisting of hydrogen, C₆₋₁₀ aryl, and C₃₋₉ heteroaryl.
 20. Thecompound of claim 1, wherein R⁶ is halogen.
 21. A compound having theformula

wherein X₃ is selected from the group consisting of O and C(R⁴)(R⁵);each of X₁ and X₂ is independently selected from a group consisting of Oand N—R; each of C_(a) and C_(b) is independently selected from thegroup consisting of an achiral center, an (S) chiral center and an (R)chiral center; R_(a) and R_(b) are (i) each independently selected fromthe group consisting of C₁₋₁₀ alkyl, C₆₋₁₀ aryl, and C₃₋₉ heteroaryl, or(ii) taken together to form a C₃₋C₄ alkylene chain which together withC_(a) and C_(b) forms a 5-membered aliphatic ring or a 6-memberedaliphatic ring; R_(c) and R_(d) are each independently selected from thegroup consisting of hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, and C₃₋₉heteroaryl, wherein R_(a), R_(b), R_(c) and R_(d) are not methyl orphenylmethyl, wherein R_(a), R_(b), R_(c) and R_(d) are not methyl orphenylmethyl; R⁶ is selected from the group consisting of halogen,hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀aryloxy, C₁₋₁₀ dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino, C₆₋₁₀diarylamino, —O—C(R⁹)═C(R⁷)(R⁸), OSO₂CF₃ and SR; R is selected from thegroup consisting of C₁₋₁₀ alkyl, C₆₋₁₀ aryl, and C₃₋₉ heteroaryl; andeach of, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, and R⁹ is independently selectedfrom the group consisting of hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉heteroaryl, C₁₋₁₀ alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino, C₁₋₁₀alkyl-C₆₋₁₀ arylamino, C₆₋₁₀ diarylamino, and halogen.
 22. A compoundhaving the formula

wherein X₃ is selected from the group consisting of O and C(R⁴)(R⁵);each of X₁ and X₂ is independently selected from the group consisting ofO and N—R; each of C_(a) and C_(b) is independently selected from thegroup consisting of an achiral center, an (S) chiral center and an (R)chiral center; R_(a) and R_(b) are (i) each independently selected fromthe group consisting of C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, or(ii) taken together to form a C₃₋C₄ alkylene chain which together withC_(a) and C_(b) forms a 5-membered aliphatic ring or a 6-memberedaliphatic ring; R_(c) and R_(d) are each independently selected from thegroup consisting of hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, and C₃₋₉heteroaryl; R⁶ is halogen; R is selected from the group consisting ofC₁₋₁₀ alkyl, C₆₋₁₀ aryl, and C₃₋₉ heteroaryl; and each of, R¹, R², R³,R⁴, R⁵, R⁷, R⁸, and R⁹ is independently selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, C₆₋₁₀ aryl, C₃₋₉ heteroaryl, C₁₋₁₀alkoxy, C₆₋₁₀ aryloxy, C₁₋₁₀ dialkylamino, C₁₋₁₀ alkyl-C₆₋₁₀ arylamino,C₆₋₁₀ diarylamino, and halogen.
 23. The compound of claim 22, wherein R⁶is chloride.